One characteristic of artherosclerosis is endothelial cell (EC) barrier dysfunction. In EC the serine protease thrombin transmits signals to the cytoskeleton that alter cell shape and lead to cell contraction and motility. Many of thrombin's actions result from activation of its receptor, PAR1, which belongs to the G protein coupled receptor family. PAR1 has a unique mechanism of activation in that thrombin cleaves the receptor and the newly exposed amino-terminus serves as its own ligand. Because the ligand is permanently present at molar concentrations researchers have found it difficult to design/discover antagonist using traditional approaches. Thus, at cue BIOtech we have implicated the carboxyl-termini of the Galpha subunits in mediating the receptor specificity and signaling. Previous work from our laboratory demonstrated that corresponding to carboxyl-terminal sequences from Galpha can compete with their appropriate heterotrimeric G protein for binding at the receptor and thus block signaling. For this application, we have identified peptides based on the carboxyl-terminal sequence of G13 that bind to PAR1. We propose testing the peptides for their affinity and specificity, as well as for their ability to block PAR1 signaling. PROPOSED COMMERCIAL APPLICATIONS: Atherosclerosis is responsible for the deaths of more Americans than any other cause, and is the leading cause of death in the western world. Hundreds of billions of dollars are spent each year treating heart disease. In 1998, it was estimated that sales of cardiovascular drugs alone were $37 billion.